Advanced Indolinone Based Protein Kinase Inhibitors

Abstract

Hydroxy carboxy pyrrolyl-indolinone derivatives have enhanced and unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.

1 . A compound represented by Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is selected from the group consisting of hydrogen, halo, (C1—C6) alkyl, (C3—C8) cycloalkyl, (C1—C6) haloalkyl, hydroxy, (C1—C6) alkoxy, amino, (C1—C6) alkylamino, amide, sulfonamide, cyano, substituted or unsubstituted (C6—C10) aryl; 
 R 2  is selected from the group consisting of hydrogen, halo, (C1—C6) alkyl, (C3—C8) cycloalkyl, (C1—C6) haloalkyl, hydroxy, (C1—C6) alkoxy, (C2—C8) alkoxyalkyl, amino, (C1—C6) alkylamino, (C6—C10) arylamino; 
 R 3  is selected from the group consisting of hydrogen, (C1—C6) alkyl, (C6—C10) aryl, (C5—C10) heteroaryl, and amide; 
 R 4 , R 5  and R 6  are independently selected from the group consisting of hydrogen and (C1—C6) alkyl; 
 each R 7  is independently selected from the group consisting of hydrogen, (C1—C6) alkyl and hydroxyl; 
 R 8  is selected from the group consisting of hydroxy, (C1—C6) O-alkyl, (C3—C8) O-cycloalkyl, and NR 9 R 10 ; where R 9  and R 10  are independently selected from the group consisting of hydrogen, (C1—C6) alkyl, (C1—C6) hydroalkyl, (C1—C6) dihydroxyalkyl, (C1—C6) alkoxy, (C1—C6) alkyl carboxylic acid, (C1—C6) alkyl phosphoric acid, (C1—C6) alkyl sulfuric acid, (C1—C6) hydroxyalkyl carboxylic acid, (C1—C6) alkyl amide, (C3—C8) cycloalkyl, (C5—C8) heterocycloalkyl, (C6—C8) aryl, (C5—C8) heteroaryl, (C3—C8) cycloalkyl carboxylic acid, or R 9  and R 10  together with N forms a (C5—C8) heterocyclic ring either unsubstituted or substituted with one or more hydroxyls, ketones, ethers, and carboxylic acids; and 
 n and m are independently 0, 1, 2, or 3; p is 1, 2, or 3; or, a pharmaceutically acceptable salt, its tautomer, a pharmaceutically acceptable salt of its tautomer, or a prodrug thereof. 
 
   
   
       2 . The compound, salt, tautomer, or prodrug according to  claim 1  selected from the group represented by the following structures: 
     
       
         
         
             
             
         
       
     
     wherein R 2  is selected from the group consisting of hydrogen and fluoro. 
   
   
       3 . The compound, salt, tautomer, or prodrug according to  claim 1  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       4 . The compound, salt, tautomer, or prodrug according to  claim 1  represented by Formula (II): 
     
       
         
         
             
             
         
       
     
     wherein R 8a  is selected from the group consisting of hydrogen, (C1—C6) alkyl, and (C3—C8) cycloalkyl. 
   
   
       5 . The compound, salt, tautomer, or prodrug according to  claim 4 , wherein:
 R 1  and R 2  are independently selected from the group consisting of hydrogen and fluoro;   R 3  and R 4  are methyl;   R 5 , R 6 , R 7  and R 8a  are hydrogen; and   n and m are independently 0, 1, or 2.   
   
   
       6 . The compound, salt, tautomer, or prodrug according to  claim 5  selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       7 . The compound, salt, tautomer, or prodrug according to  claim 5  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       8 . The compound, salt, tautomer, or prodrug according to  claim 5  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       9 . A compound, salt, tautomer, or prodrug according to  claim 1  represented by Formula (III): 
     
       
         
         
             
             
         
       
     
     wherein R 8a  is selected from the group consisting of hydrogen, (C1—C6) alkyl, and (C3—C8) cycloalkyl. 
   
   
       10 . The compound, salt, tautomer, or prodrug according to  claim 9 , wherein:
 R 1  and R 2  are independently selected from the group consisting of hydrogen and fluoro;   R 3  and R 4  are methyl;   R 5 , R 6 , and R 8a  are hydrogen; and   n and p are independently 1, or 2.   
   
   
       11 . The compound, salt, tautomer, or prodrug according to  claim 10  selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       12 . The compound, salt, tautomer, or prodrug according to  claim 10  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       13 . The compound, salt, tautomer, or prodrug according to  claim 10  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       14 . The compound, salt, tautomer, or prodrug according to  claim 10  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       15 . A compound, salt, tautomer, or prodrug according to  claim 9  represented by Formula (IIIa): 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  and R 2  are independently selected from the group consisting of hydrogen and fluoro; 
 R 3  and R 4  are methyl; 
 R 5 , R 6 , and R 8a  are hydrogen; and 
 n and p are 2. 
 
   
   
       16 . A compound, salt, tautomer, or prodrug according to  claim 15  represented by Formula (IIIb): 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  and R 2  are independently selected from the group consisting of hydrogen and fluoro; and 
 R 3  and R 4  are methyl. 
 
   
   
       17 . A compound, salt, tautomer, or prodrug according to  claim 1  represented by Formula (IV): 
     
       
         
         
             
             
         
       
     
     wherein R 8  is NR 9 R 10 . 
   
   
       18 . The compound, salt, tautomer, or prodrug of  claim 17 , wherein:
 R 1  and R 2  are independently selected from the group consisting of hydrogen, halo, cyano;   R 3 , R 4 , R 5  and R 6  are independently hydrogen or (C1—C6) )alkyl;   R 7  is hydrogen, or hydroxyl;   n, and p are independently 1, or 2;   m is 0 or 1; and   R 9  and R 10  are selected from the group consisting of hydrogen, (C1—C6) alkyl, (C1—C6) hydroxyalkyl, (C1—C6) dihydroxyalkyl, (C1—C6) alkoxy, (C1—C6) alkyl carboxylic acid, (C1—C6) alkyl phosphoric acid, (C1—C6) alkyl sulfuric acid, (C1—C6) hydroxyalkyl carboxylic acid, (C1—C6) alkyl amide, (C3—C8) cycloalkyl, (C5—C8) heterocycloalkyl, (C6—C8) aryl, (C5—C8) heteroaryl, (C3—C8) cycloalkyl carboxylic acid, or R 9  and R 10  together with N forms a (C5—C8) heterocyclic ring either unsubstituted or substituted with one or more hydroxyls, ketones, ethers, and carboxylic acids.   
   
   
       19 . The compound, salt, tautomer, or prodrug according to  claim 18  selected from the group represented by the following structures: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       20 . The compound, salt, tautomer, or prodrug according to  claim 18  selected from the group represented by the following structures: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       21 . The compound, salt, tautomer, or prodrug according to  claim 18  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       22 . The compound, salt, tautomer, or prodrug according to  claim 18  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       23 . The compound, salt, tautomer, or prodrug according to  claim 18  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       24 . The compound, salt, tautomer, or prodrug according to  claim 18  represented by the following structure: 
     
       
         
         
             
             
         
       
     
     wherein n is 0, 1, or 2. 
   
   
       25 . The compound, salt, tautomer, or prodrug according to  claim 24  selected from the group represented by the following structures: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       26 . The compound, salt, tautomer, or prodrug according to  claim 24  selected from the group represented by the following structures: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       27 . The compound, salt, tautomer, or prodrug according to  claim 18  selected from the group represented by the following structures: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       28 . The compound, salt, tautomer, or prodrug according to  claim 18  selected from the group represented by the following structures: 
     
       
         
         
             
             
         
       
     
   
   
       29 . The compound, salt, tautomer, or prodrug according to  claim 18  selected from the group represented by the following structures: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 2  is selected from the group consisting of hydrogen and fluoro; and 
 R 8  is selected from the group consisting of radicals represented by the following structures: 
 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       30 . (canceled) 
   
   
       31 . A method for the modulation of the catalytic activity of a protein kinase with a compound or salt of any one of  claims 1 - 29 . 
   
   
       32 . The method of  claim 31 , wherein said protein kinase is selected from the group consisting of VEGF receptors and PDGF receptors.